Prophylactic treatment of migraine

ABSTRACT

The present invention provide methods and compositions for the prophylactic, targeted prophylactic, acute or acutely targeted, or subacute treatment of migraine. Representative methods include an embodiment where a patient is regularly given a therapeutically effective amount of a cyclooxygenase-2 inhibitor, an embodiment where a patient is co-administered a therapeutically effective amount of a combination of a cyclooxygenase-2 inhibitor and acetylsalicylic acid and an embodiment where a patient is co-administered a therapeutically effective amount of a combination of at cyclooxygenase-2 inhibitor and a 5-HT agonist. Representative compositions; include cyclooxygenase-2 inhibitors, HT-5 agonists, acetylsalicylic acid and combinations thereof.

BACKGROUND

[0001] Headaches are among the most common of medical problems. Somepeople have headaches often, while for others headaches occurinfrequently. Both chronic and recurring headaches may be painful anddistressing. Most headaches are grouped in the following categories:“tension” headache, migraine, or headache of undetermined etiology. Adoctor can usually determine the likely cause of headache from thepatient's medical history and a physical examination. A headache thatlasts approximately 4 to 72 hours or longer, may be throbbing, of anylevel of intensity, often unilateral and/or worsened by exertion, andoften associated with nausea, vomiting, sensitivity to light, sound, orsmell may be (and often is) due to migraine. Some patients willexperience other symptoms before, after, or during the development of afull-fledged migraine. These symptoms of migraine can also be difficultand distressing for the patient and may occur with or without headache.

[0002] Some estimate that 20 million or more Americans have migraine.Migraine usually begins between the ages of 10 and 40, but it can beginat any age between infancy and the seventh decade. Most studies show afemale preponderance of 60-70%. Migraine often remits or changescharacter during the sixth decade of life. Greater than one-half ofafflicted individuals have a positive family history of migraine. Themechanism for migraine has not been well defined, although a number oftheories have been advanced. Migraine may result from the response of apatient to the interaction of a number of factors including inheritedsusceptibility. Predisposing factors may include increasing or remittingstress (or emotional upset), hormonal factors including estrogen,certain medications, glare, skipped meals, and numerous dietary factors.

[0003] There is no reliable, economically practical laboratory testavailable to aid the clinician in the diagnosis of migraine. However,there are some characteristic features of migraine headache which areoften helpful. Some 5 to 30 minutes before the headache begins (a periodcalled the aura or prodrome), symptoms of a change in mood,irritability, restlessness, nausea, or a change in appetite occur inabout 20 percent of patients. A similar percentage of patients losevision in a specific area (called a blind spot or scotoma) or seejagged, shimmering, or flashing lights. Less commonly, images aredistorted; for instance, objects appear smaller or larger than they are.Some patients experience tingling sensations or, rarely, weakness in anarm or leg. Usually these symptoms disappear shortly before the headachebegins, but sometimes they merge with it. The pain of a migraine may befelt on either side of the head or over the entire head. Occasionally,the hands and feet may become cold and turn blue. In most of those whohave a prodrome, the pattern and headache location remain essentiallythe same with each migraine. Migraine headaches may occur frequently forlong periods in some patients. On the other hand, in some patients themigraine may remit for weeks, months or even years.

[0004] Migraine attacks may last for a period of four hours to severaldays if not treated. For some, the headaches are mild and easilyrelieved with nonprescription analgesics. Quite often, migraineheadaches are severe and temporarily disabling, especially whenaccompanied by nausea, vomiting, and discomfort from bright light.

[0005] A variety of abortive drugs are used for the acute treatment ofmigraines. For example, one class of drugs that activate serotoninreceptors (5-hydroxytryptamine agonists or 5-HT agonists) mediatevasoconstriction and can abort migraine pain in about 70% of patients.The drug sumatriptan is available in oral, nasal spray and subcutaneousinjection forms. Subcutaneous dosing is more effective but has greaterpotential adverse effects, which include flushing, nausea, esophagealconstriction, and, rarely, coronary artery constriction. Other known5-HT agonists include eletriptan, naratriptan, rizatriptan andzolmitriptan. These oral agents may be less effective in the relief ofacute migraine, however, the side effects of these agents arepotentially less severe. The drug naratriptan is available in tabletform. Ergot alkaloid derivatives, such as ergotamine tartrate anddihydroergotamine, in oral and parenteral preparations have been used.Dopamine antagonist antiemetics, such as metoclopramide andprochlorperazine, may also be effective. It has been reported thatanalgesics should be used sparingly. They are effective in some patientsbut cause rebound headache with dose escalation in others. Reboundheadache may be induced by repetitive and on-going overuse of acuteheadache medication. Some nonsteroidal anti-inflammatory agents (NSAIDs)may be suitable for mild to moderate headaches. Opioids are generallyavoided except under special circumstances and strict control.

[0006] Currently available abortive agents are often associated withrecurrent migraine (triptans), rebound migraine (analgesics), or lack ofsufficient efficacy when used with a convenient and practical method ofadministration (non-injected triptans). A need exists for a targetedprophylactic, acute, or subacute treatment of migraine that cansubstantially and reliably, with few or no side effects, diminish thelikelihood of a patient being affected by disabling migraine symptomsduring an important period of time and/or activity for that individual.

[0007] Some drugs taken every day may prevent migraine attacks fromrecurring. A beta-blocker, propranolol, provides long-term relief forabout half the people who have frequent migraine headaches. The calciumchannel blocker, verapamil, is effective for a few people. Recently, theantisiezure drug, divalproex, has been found to reduce the frequency ofmigraine headaches when taken daily. Methysergide is another preventivedrug, but it must be taken intermittently because is can unpredictablecause a serious complication called retroperitoneal fibrosis, aformation of scar tissue deep within the abdomen, which can block bloodsupply to vital organs. Therefore, the use of this drug must be closelysupervised by a medical provider.

[0008] Unfortunately, many patients experience significant side effectsand/or lack of efficacy with the available and commonly prescribedprophylactic medications for migraine. A need exists for a prophylacticand/or targeted prophylactic treatment of migraine that uses active andeffective agents or drugs with no or few complications or side effects.

SUMMARY OF THE INVENTION

[0009] The present invention provides a prophylactic, targetedprophylactic, acute or subacute treatment of migraine that significantlyreduces undesired risks or overcomes the problems of side effectsassociated with current methods of treatment and that providesalternative methodologies for patients that cannot be treated or helpedwith current methods.

[0010] In one embodiment of this invention, a patient is regularly givena therapeutically effective amount of a cyclooxygenase-2 inhibitor forprophylactic, targeted prophylactic or acute, or subacute treatment ofmigraine. In another embodiment of this invention, a patient isco-administered a therapeutically effective amount of a combination of acyclooxygenase-2 inhibitor and acetylsalicylic acid (aspirin). Thiscombination is effective when given on an acute, subacute, prophylacticor targeted prophylactic basis. Also, a prophylactic low-dose regimenusing an alternate day regimen including a cyclooxygenase-2 inhibitorand aspirin is effective in the prophylactic treatment of migraine. Inthis embodiment, the potential side effects of both medications oragents are reduced when used in combination or on alternate days.Further, this combination may be useful in conditions other thanmigraine. In yet another embodiment of this invention, a patient isco-administered a therapeutically effective amount of a combination of acyclooxygenase-2 inhibitor and a 5-HT agonist for the targetedprophylactic or acute treatment of migraine.

[0011] Still another embodiment of this invention includes apharmaceutical composition in unit dosage form that contains atherapeutically effective amount of a cyclooxygenase-2 inhibitor andacetylsalicylic acid as well as a pharmaceutically acceptable carrier.The unit dosage forms of this embodiment may be provided in the form ofa kit that includes both a cyclooxygenase-2 inhibitor andacetylsalicylic acid, either as two separate unit dosage forms orcombined as a single unit dosage form.

[0012] Cyclooxygenase-2 inhibitors that that are suitable for use in theinvention include compounds that selectively inhibit cyclooxygenase-2that are reported in the art or that are obvious variants. Oneacceptable cyclooxygenase-2 inhibitor includes compounds represented byFormula 1.

[0013] In Formula 1, variable R₁ represents lower alkylsulfonyl orsulfamy and variable R₂ represents alkyl, cycloalkyl, aryl, mono-, di-or trisubstituted heteroaryl or benzoheteroaryl. A representativecompound is rofecoxib.

[0014] Another acceptable cyclooxygenase-2 inhibitor includes compoundsrepresented by Formula 2.

[0015] In Formula 2, variable R₁ represents lower alkylsulfonyl orsulfamy, variable R₂ represents alkyl, haloalkyl or halogen, variable R₃represents hydrogen, lower alkyl or haloalkyl, and variable R₄represents cycloalkyl, cycloalkenyl, aryl and substituted aryl. Arepresentative compound is celecoxib.

[0016] 5-HT agonists that are suitable for use in the present inventioninclude compounds that selectively effect 5-HT (5-hydroxytryptamine orserotonin) receptors of the central nervous and vascular systems. Thisclass of compounds has been recognized as useful in abortive migrainetherapy. Representative compounds in this class include sumatriptan,eletriptan, rizatriptan, frovatriptan, almotriptan, zolmitriptan, andnaratriptan as well as ergot alkaloids and related compounds such asdihydroergotamine mesylate, ergotamine tartrate, ergonovine maleate,ergoloid mesylates such as dihydroergocornine, dihydroergocristine,dihydroergocryptine, dihydro-.alpha.-ergocryptine,dihydro-.beta.-ergocryptine and dihydroergotamine mesylate.

DETAILED DESCRIPTION

[0017] This invention provides a method for prophylactically (longterm), targeted prophylactically, acutely targeted, acutely orsubacutely treating migraine. This method of treatment includesadministering a therapeutically effective amount of a cyclooxygenase-2inhibitor, either alone or combined with acetylsalicylic acid, to apatient. Further, an alternative method includes administering atherapeutically effective amount of a cyclooxygenase-2 inhibitorcombined with a HT-5 agonist to a patient.

[0018] Compounds that are cyclooxygenase-2 inhibitors and methods forthe preparation of these compounds have been reported in the art. See,for example, U.S. Pat. Nos. 5,380,738; 5,344,991; 5,393,790; 5,466,823;5,434,178; 5,474,995; 5,510,368; 5,521,207, 5,604,260 and 6,248,745 andinternational applications WO96/06840, WO96/03388, WO96/03387,WO95/15316, WO94/15932, WO94/27980, WO95/00501, WO94/13635, WO94/20480and WO94/26731. Representative compounds that are commercially availableinclude rofecoxib and celecoxib. These two compounds are sold under thetradenames VIOXX (Merck & Co., Inc., West Point, Pa.) and CELEBREX (G.D. Searle & Co., Chicago, Ill.), respectively.

[0019] The term “cyclooxygenase-2 inhibitor” includes compounds thatselectively inhibit cyclooxygenase-2 over cyclooxygenase- 1. Preferably,the compounds have a cyclooxygenase-2 inhibition of less than about 0.5.mu.M, and also have a selectivity ratio of cyclooxygenase-2 inhibitionover cyclooxygenase-1 inhibition of at least 50, and more preferable ofat least 100. Even more preferably, the compounds have acyclooxygenase-1 IC₅₀ of greater than about 1 .mu.M, and more preferableof greater than 20 .mu.M. This selectivity may indicate an ability toreduce the incidence of common NSAID-induced side effects when used. Useof a cyclooxygenase-2 inhibitor agent is intended to includeadministration of one or more agents in a sequential manner in a regimenthat will provide beneficial effects of the drug combination, and isintended as well to include co-administration of these agents in asubstantially simultaneous manner, such as in a single capsule having afixed ratio of these active agents or in multiple, separate capsules foreach agent.

[0020] Suitable classes of compounds that inhibit cyclooxygenase-2includes compounds represented by Formulas 1 and 2. Suitable embodimentsof cyclooxygenase-2 inhibitors are represented by Formula 1.

[0021] wherein R₁ is lower alkylsulfonyl or sulfamy; and

[0022] R₂ is alkyl, cycloalkyl, aryl, mono-, di- or trisubstitutedheteroaryl or benzoheteroaryl.

[0023] Suitable embodiments further include compounds represented byFormula 1 wherein

[0024] R₁ is lower alkylsulfonyl; and

[0025] R₂ is mono- or disubstitued phenyl.

[0026] Still other embodiments of cyclooxygenase-2 inhibitors arecompounds represented by Formula 2.

[0027] wherein R₁ is lower alkylsulfonyl or sulfamy;

[0028] R₂ is alkyl, haloalkyl or halogen;

[0029] R₃ is hydrogen, lower alkyl or haloalkyl; and

[0030] R₄ is cycloalkyl, cycloalkenyl, aryl or substituted aryl. Furtherembodiments include compounds represented by Formula 2 wherein R₁ issulfamy; R₂ is haloalkyl; R₃ is hydrogen or lower alkyl; and R₄ is arylor substituted aryl.

[0031] The terms that are used in the formulas have the followingdefinitions:

[0032] The term “hydrogen” means a single hydrogen atom.

[0033] The term “alkyl” means linear or branched radicals having one toabout twenty carbon atoms or, preferably, one to about twelve carbonatoms. Some alkyl radicals are “lower alkyl” radicals having one toabout ten carbon atoms. Others are lower alkyl radicals having one toabout six carbon atoms. Examples of such radicals include methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl,iso-amyl, and hexyl.

[0034] The term “cycloalkyl”, means saturated carbocyclic radicalshaving three to twelve carbon atoms. Some cycloalkyl radicals are “lowercycloalkyl” radicals having three to about eight carbon atoms. Examplesof such radicals include cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl.

[0035] The term “cycloalkenyl” means partially unsaturated carbocyclicradicals having three to twelve carbon atoms. Some cycloalkenyl radicalsare “lower cycloalkenyl” radicals having four to about eight carbonatoms. Examples of such radicals include cyclobutenyl, cyclopentenyl,cyclopentadienyl, and cyclohexenyl.

[0036] The term “halo” means halogen radicals such as fluorine,chlorine, bromine or iodine radicals.

[0037] The term “haloalkyl” means radicals wherein any one or more ofthe alkyl hydrogen atoms is substituted with halogen radical as definedabove such as monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. Amonohaloalkyl radical, for one example, may have either an iodine,bromine, chlorine or fluorine atom within the radical. Dihalo andpolyhaloalkyl radicals may have two or more of the same halogen radicalsor a combination of different halogen radicals. Examples of haloalkylradicals include fluoromethyl, difluoromethyl, trifluoromethyl,chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl,heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl,difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.

[0038] The terms “alkoxy” and “alkyloxy” mean linear or branchedoxygen-containing radicals each having alkyl portions of one to aboutten carbon atoms. Some alkoxy radicals are “lower alkoxy” radicalshaving one to six carbon atoms. Examples of such radicals includemethoxy, ethoxy, propoxy, butoxy and tert-butoxy.

[0039] The term “alkoxyalkyl” means alkyl radicals having one or morealkoxy radicals attached to the alkyl radical, that is, to formmonoalkoxyalkyl and dialkoxyalkyl radicals. The “alkoxy” radicals may befurther substituted with one or more halogen radicals such as fluorine,chlorine or bromine radicals to provide haloalkoxy radicals. Somehaloalkoxy radicals are “lower haloalkoxy” radicals having one to sixcarbon atoms and one or more halogen radicals. Examples of such radicalsinclude fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy,fluoroethoxy and fluoropropoxy.

[0040] The term “aryl” means a carbocyclic aromatic system containingone, two or three rings where these rings may be attached together in apendent manner or may be fused. For example, the term “aryl” includesaromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indaneand biphenyl. Aryl moieties may also be substituted at a substitutableposition with one or more substituents selected independently fromalkyl, haloalkyl, alkoxyalkyl, alkylaminoalkyl, carboxyalkyl,alkoxycarbonylalkyl, aminocarbonylalkyl, alkoxy, arylalkoxy, hydroxyl,amino, halo, nitro, alkylamino, acyl, cyano, carboxy, aminocarbonyl,thioalkyl, alkoxycarbonyl and arylalkoxycarbonyl.

[0041] The term “heteroaryl” means unsaturated, saturated, unsubstitutedand substituted heterocyclyl radicals.

[0042] The term “benzaheteroaryl” means heteroaryl rings fused to abenzene ring.

[0043] The term “alkylthio” means radicals containing a linear orbranched alkyl radical of one to about ten carbon atoms attached to adivalent sulfur atom. Some alkylthio radicals are “lower alkylthio”radicals having alkyl radicals of one to six carbon atoms. Examples ofsuch lower alkylthio radicals are methylthio, ethylthio, propylthio,butylthio and hexylthio.

[0044] The term “lower alkylsulfonyl” means radicals having one to sixcarbon atoms. Examples of such lower alkylsulfonyl radicals includemethylsulfonyl, ethylsulfonyl and propylsulfonyl. The “alkylsulfonyl”radicals may be further substituted with one or more halogen radicalssuch as fluorine, chlorine or bromine radicals atoms to providehaloalkylsulfonyl radicals.

[0045] The terms “sulfamyl”, “aminosulfonyl” and “sulfonamidyl”, denotesthe radical NH₂O₂S—.

[0046] The term “acyl” denotes a radical provided by the residue afterremoval of hydroxyl from an organic acid.

[0047] The terms “carboxy” or “carboxyl”, whether used alone or withother terms, such as “carboxyalkyl”, denotes —CO₂H.

[0048] The term “carboxyalkyl” means alkyl radicals substituted with acarboxy radical.

[0049] The term “alkoxycarbonyl” means a radical containing an alkoxyradical attached via an oxygen atom to a carbonyl radical.

[0050] The term “alkylamino” denotes amino groups which have beensubstituted with one or two alkyl radicals.

[0051] The term “alkylaminoalkyl” means radicals having one or morealkyl radicals attached to an aminoalkyl radical.

[0052] The term “pharmaceutically-acceptable salts” means salts commonlyused to form alkali metal salts and to form addition salts of free acidsor free bases. The nature of the salt is not critical, provided that itis pharmaceutically acceptable. Suitable pharmaceutically acceptableacid addition salts of compounds of Formulas 1 and 2 may be preparedfrom an inorganic acid or from an organic acid. Examples of suchinorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric,carbonic, sulfuric and phosphoric acid. Appropriate organic acids may beselected from aliphatic, cycloaliphatic, aromatic, heterocyclyl,carboxylic and sulfonic classes of organic acids, examples of which areformic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic,tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic,aspartic, glutamic, benzoic, anthranilic, mesylic, p-hydroxybenzoic,phenylacetic, mandelic, embonic (pamoic), methanesulfonic,ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic,2-hydroxyethanesulfonic, sulfanilic, stearic, cyclohexylaminosulfonic,algenic, .beta.-hydroxybutyric, salicylic, galactaric and galacturonicacid. Suitable pharmaceutically-acceptable base addition salts ofcompounds of Formulas 1 and 2 include metallic salts made from aluminum,calcium, lithium, magnesium, potassium, sodium and zinc or organic saltsmade from N,N′-dibenzylethylenediamine, chloroprocaine, choline,diethanolamine, ethylenediamine, meglumine (N-methylglucamine) andprocaine. All of these salts may be prepared by conventional means fromthe corresponding compounds of Formulas 1 and 2 by reacting, forexample, the appropriate acid or base with the compounds of Formulas 1and 2.

[0053] 5-HT agonists that are suitable for use in the present inventioninclude compounds that selectively effect 5-HT (5-hydroxytryptamine orserotonin) receptors of the central nervous and vascular systems. Thisclass of compounds has been recognized as useful in migraine therapy.Suitable compounds in this class include sumatriptan, eletriptan,rizatriptan, frovatriptan, almotriptan, zolmitriptan, and naratriptan aswell as ergot alkaloids and related compounds such as dihydroergotaminemesylate, ergotamine tartrate, ergonovine maleate, ergoloid mesylatessuch as dihydroergocomine, dihydroergocristine, dihydroergocryptine,dihydro-.alpha.-ergocryptine, dihydro-.beta.-ergocryptine anddihydroergotamine mesylate.

[0054] The term “5-HT agonist” means all types of HT agonists, includingbut not limited to 5-HT₁-like agonists, 5-HT_(1B) agonists, and5-HT_(1D) agonists. Specific compounds that have been identified for usein migraine therapy are reported in U.S. Pat. No. 6,060,499.Representative compounds include sumatriptan succinate and related 5-HTagonist heterocyclic compounds reported in U.S. Pat. No. 4,816,470 toDowle et al.

[0055] Representative 5-HT agonist compounds that are commerciallyavailable include sumatriptan succinate, available under the tradenameIMITREX, and naratriptan hydrochloride, available under the tradenameAMERGE, both available from GlaxoWellcome Inc., Research Triangle Park,N.C.

[0056] Other 5-HT agonist compounds include ergot alkaloids and relatedcompounds such as dihydroergotamine mesylate (DHE 45), ergotaminetartrate, ergonovine maleate, ergoloid mesylates such asdihydroergocornine, dihydroergocristine, dihydroergocryptine,dihydro-.alpha.-ergocryptine and dihydro-.beta.-ergocryptine anddihydroergotamine mesylate.

[0057] Still other compounds include eletriptan reported in EPApplication 0 379 314, Allelix ALX 1323; rizatriptan, frovatriptan,almotriptan, zolmitriptan and naratriptan. Related pharmacologicalcompounds are also included within the scope of this invention.

[0058] Prophylactic or targeted prophylactic regimens are expected to beparticularly relevant to the treatment of persons who have suffered aprevious episode of, or are otherwise considered to be at increased riskof, migraine. The indications for preventative treatment of migrainehave been published by the American Academy of Neurology. The “targetedprophylactic” approach is especially relevant for persons with frequent,recurring migraine symptoms who anticipate critical activities duringwhich it is very important to prevent or minimize their migraine-relatedsymptoms. For some of these patients, it is possible that early,premonitory or actual migraine symptoms will be evident at the time ofadministration of the agent or agents to be used for treatment. In thiscase, the treatment is actually acute or abortive but may also be termed“acutely targeted” if the goal is to eliminate or substantially reducethe migraine symptoms during a particular time or activity for apatient. In other cases, there will be no actual or premonitory symptomsof migraine when this agent or agents are used for targeted prophylaxis.This dosing strategy is very useful for those persons with frequent,recurring high demand activities that have frequent migraine symptoms.

[0059] Persons at risk of developing a migraine condition generallyinclude those having a family history of migraine, or those diagnosed oridentified by a licensed physician to be particularly susceptible todeveloping migraine.

[0060] The phrase “therapeutically effective” is intended to qualify theamount of each active agent or compound for use in a combination therapywhich will achieve the goal of improvement in migraine treatment ortherapy or reduced frequency or incidence of migraine over treatment ofeach agent or compound by itself, while avoiding adverse side effectstypically associated with alternative therapies.

[0061] For appropriate therapeutic indications, the dosage administeredwill vary with the compound employed, the mode of administration and thetreatment desired. However, in general, satisfactory results areobtained when the compounds are administered at a daily dosage of thesolid form of between 1 mg and 2000 mg per day.

[0062] A unit dose of about 0.01 to 100 mg/kg body weight, preferablybetween about 0.1 and about 50 mg/kg body weight and most preferablyfrom about 1 to 20 mg/kg body weight, may be appropriate.

[0063] The amount of the compound actually administered will bedetermined by a physician in light of the relevant circumstancesincluding the condition to be treated, the choice of compound to beadministered, the age, weight, and response symptoms, and the chosenroute of administration. Therefore the dosage ranges are not intended asa limitation to the scope of the invention.

[0064] The agents or compounds of this invention may be used on theirown, or preferably as a pharmaceutical composition in which thecompounds or derivatives are in admixture with a pharmaceuticallyacceptable adjuvant, diluent or carrier in a form appropriate forenteral or parenteral administration. The pharmaceutical compositionpreferably comprises less than 80% and more preferably less than 50% ofthe agent, compound or derivative. Examples of suitable adjuvants,diluents and carriers are well known and include microcrystallinecellulose, calcium phosphate, diatomaceous earth, a sugar such aslactose, dextrose or mannitol, talc, stearic acid, starch, sodiumbicarbonate and/or gelatin.

[0065] Also included within this invention is a class of pharmaceuticalcompositions comprising the active agents or compounds of thiscombination therapy in association with one or more non-toxic,pharmaceutically-acceptable carriers and/or diluents and/or adjuvants(collectively referred to as “carrier” materials) and, if desired, otheractive ingredients. The active compounds of the present invention may beadministered by any suitable route, preferably in the form of apharmaceutical composition adapted to such a route, and in a doseeffective for the treatment intended. The active compounds andcomposition may, for example, be administered orally, intravascularly,intraperitoneally, subcutaneously, intramuscularly or topically.

[0066] For oral administration, the pharmaceutical composition may be inthe form of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient. Examplesof such dosage units are tablets or capsules. The active ingredient mayalso be administered by injection as a composition where, for example,saline, dextrose or water may be used as a suitable carrier. Fortherapeutic purposes, the active compounds of this combination inventionare ordinarily combined with one or more adjuvants appropriate to theindicated route of administration. If administered orally, the compoundsmay be admixed with lactose, sucrose, starch powder, cellulose esters ofalkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesiumstearate, magnesium oxide, sodium and calcium salts of phosphoric andsulfuric acids, gelatin, acacia gum, sodium alginate,polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted orencapsulated for convenient administration. Such capsules or tablets maycontain a controlled-release formulation as may be provided in adispersion of active compound in hydroxy-propylmethyl cellulose.Formulations for parenteral administration may be in the form of aqueousor non-aqueous isotonic sterile injection solutions or suspensions.These solutions and suspensions may be prepared from sterile powders orgranules having one or more of the carriers or diluents mentioned foruse in the formulations for oral administration. The compounds may bedissolved in water, polyethylene glycol, propylene glycol, ethanol, cornoil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodiumchloride, and/or various buffers. Other adjuvants and modes ofadministration are well and widely known in the pharmaceutical art.

[0067] The following examples further describe the method of the presentinvention. These examples illustrate alternative embodiments of theinvention and do not limit the scope of the appended claims.

EXAMPLES Example 1

[0068] A patient with an established history of recurrent migraine wastreated with a daily oral dose of 25 mg. of VIOXX (rofecoxib tablets,Merck & Co, Inc., West Point, Pa.). The patient was free of migrainesymptoms during the first week of use and noticed a reduced intensity ofthe symptoms of subsequent migraines as well as a reduced frequency ofmigraines during the treatment period of three to four weeks whiletaking the VIOXX tablets.

Example 2

[0069] A patient with an established history of recurrent migraine wastreated with a daily oral dose of 25 mg of VIOXX (rofecoxib tablets,Merck) and 325 mg of enteric aspirin tablets (over the counter bufferedaspirin). The patient noted a lower incidence and intensity of migrainesymptoms while taking the combination of VIOXX and aspirin tablets.

Example 3

[0070] A patient with an established history of recurrent migraine wastreated with a daily oral dose of 12.5 mg of VIOXX (rofecoxib tablets,Merck & Co, Inc., West Point, Pa.) and 162.5 mg aspirin tablets (overthe counter aspirin) for about four weeks. Then the patient switched toan every other day regimen of 12.5-25 mg VIOXX tablets alternating with325 mg aspirin tablets. The patient noted a lower incidence andintensity of migraine symptoms during the treatment period of about 52weeks. He also noted a significant reduction in the use of 5-HT receptoragonists (IMITREX injections and nasal spray, Glaxo Wellcome Inc.,Research Triangle Park, N.C. and AMERGE tablets, Glaxo Wellcome) whiletaking the combination of VIOXX and aspirin tablets.

Example 4

[0071] A patient with an established history of recurrent migraine wastreated with a daily oral dose of 200 mg of CELEBREX (celecoxibcapsules, G. D. Searle & Co., Chicago, Ill.) The patient was free ofmigraine symptoms during the treatment period of ten to fourteen daysand noticed a reduced intensity of the symptoms of a subsequent migrainewhile taking the CELEBREX capsules.

Example 5

[0072] A patient with an established history of migraine brought on byglare associated with an opthalmic operating room microscope was treatedwith 6 mg of IMITREX by injection (Glaxo Wellcome Inc.), and an oraldose of 12.5-25 mg of VIOXX (Merck & Co, Inc.) the night before ascheduled opthalmic operation. The patient was free of migraine symptomsbefore, during and after the scheduled operation after targetedprophylactic treatment with the combination of IMITREX injection andVIOXX tablet treatment on many occasions. There were other occasionswhere there were migraine symptoms present at a greatly reducedintensity as compared to a full-fledged migraine, so that he was able tofunction effectively.

1. A method of treating migraine comprising administering to a patienttherapeutically effective amount of a combination comprising acyclooxygenase-2 inhibitor and acetylsalicylic acid.
 2. The method ofclaim 1 wherein the cyclooxygenase-2 inhibitor is a compound of Formula1

wherein R₁ is lower alkylsulfonyl or sulfamy; and R₂ is alkyl,cycloalkyl, aryl, mono-, di- or trisubstituted heteroaryl orbenzoheteroaryl.
 3. The method of claim 2 wherein the cyclooxygenase-2inhibitor is a compound of Formula 1 wherein is lower alkylsulfonyl; andR₂ is mono- or disubstitued phenyl.
 4. The method of claim 3 wherein thecyclooxygenase-2 inhibitor is rofecoxib.
 5. The method of claim 1wherein the cyclooxygenase-2 inhibitor is a compound of Formula 2

wherein is lower alkylsulfonyl or sulfamy; R₂ is alkyl, haloalkyl orhalogen; R₃ is hydrogen, lower alkyl or haloalkyl; and R₄ is cycloalkyl,cycloalkenyl, aryl or substituted aryl.
 6. The method of claim 5 whereinthe cyclooxygenase-2 inhibitor is a compound of Formula 2 wherein R₁ issulfamy; R₂ is haloalkyl; R₃ is hydrogen, or lower alkyl; and R₄ is arylor substituted aryl.
 7. The method of claim 6 wherein thecyclooxygenase-2 inhibitor is celecoxib.
 8. A pharmaceutical compositionto prophylactically treat migraine in unit dose form comprising atherapeutically effective combination of a cyclooxygenase-2 inhibitor,acetylsalicylic acid and a pharmaceutically acceptable carrier.
 9. Thecomposition of claim 8 wherein the cyclooxygenase-2 inhibitor is acompound of Formula 1

wherein R₁ is lower alkylsulfonyl or sulfamy; and R₂ is alkyl,cycloalkyl, aryl, mono-, di- or trisubstituted heteroaryl orbenzoheteroaryl.
 10. The composition of claim 9 wherein thecyclooxygenase-2 inhibitor is a compound of Formula 1 wherein is loweralkylsulfonyl; and R₂ is mono- or disubstitued phenyl.
 11. Thecomposition of claim 10 wherein the cyclooxygenase-2 inhibitor isrofecoxib.
 12. The composition of claim 8 wherein the cyclooxygenase-2inhibitor is a compound of Formula 2 wherein is lower alkylsulfonyl orsulfamy; R₂ is alkyl, haloalkyl or halogen; R₃ is hydrogen, lower alkylor haloalkyl; and R4 is cycloalkyl, cycloalkenyl, aryl or substitutedaryl.
 13. The composition of claim 12 wherein the cyclooxygenase-2inhibitor is a compound of Formula 2 wherein R₁ is sulfamy; R₂ ishaloalkyl; R₃ is hydrogen, or lower alkyl; and R₄ is aryl or substitutedaryl.
 14. The composition of claim 13 wherein the cyclooxygenase-2inhibitor is celecoxib.
 15. A method of prophylactically or targetedprophylactically treating migraine comprising administering to a patienta therapeutically effective amount of a cyclooxygenase-2 inhibitor. 16.The method of claim 15 wherein the cyclooxygenase-2 inhibitor is acompound of Formula 1

wherein R₁ is lower alkylsulfonyl or sulfamy; and R₂ is alkyl,cycloalkyl, aryl, mono-, di- or trisubstituted heteroaryl orbenzoheteroaryl.
 17. The method of claim 16 wherein the cyclooxygenase-2inhibitor is a compound of Formula 1 wherein is lower alkylsulfonyl; andR₂ is mono- or disubstitued phenyl.
 18. The method of claim 17 whereinthe cyclooxygenase-2 inhibitor is rofecoxib.
 19. The method of claim 15wherein the cyclooxygenase-2 inhibitor is a compound of Formula 2

wherein is lower alkylsulfonyl or sulfamy; R₂ is alkyl haloalkyl orhalogen; R₃ is hydrogen, lower alkyl or haloalkyl; and R₄ is cycloalkyl,cycloalkenyl, aryl or substituted aryl.
 20. The method of claim 19wherein the cyclooxygenase-2 inhibitor is a compound of Formula 2wherein R₁ is sulfamy; R₂ is haloalkyl; R₃ is hydrogen, or lower alkyl;and R₄ is aryl or substituted aryl.
 21. The method of claim 20 whereinthe cyclooxygenase-2 inhibitor is celecoxib.
 22. A kit to provide a drugtreatment regimen to a patient comprising one or more pharmaceuticalcompositions according to any of claims 8-15.
 23. A method of a targetedprophylactic or acutely targeted treatment of migraine comprisingadministering to a patient therapeutically effective amount of acombination comprising a cyclooxygenase-2 inhibitor and an HT-5 agonist.24. The method of claim 23 wherein the cyclooxygenase-2 inhibitor is acompound according to claims 2-7.
 25. The method of claim 23 wherein theHT-5 agonist is sumatriptan, eletriptan, rizatriptan, frovatriptan,almotriptan, zolmitriptan, or naratriptan.
 26. The method of claim 25wherein the HT-5 agonist is sumatriptan succinate or naratriptanhydrochloride.
 27. The method of claim 23 wherein the HT-5 agonist is anergot alkaloid, a dihydroergotamine mesylate, an ergotamine tartrate, anergonovine maleate, or an ergoloid mesylates.
 28. A method of atreatment of migraine comprising administering to a patienttherapeutically effective amount of a combination comprising acyclooxygenase-2 inhibitor, an HT-5 agonist and acetylsalicyclic acid.